UNAIDS estimates that 14,000 persons are newly infected with HIV-1 every day throughout the world, of which one half are between the ages of 15 and 24. New transmission occurs despite widespread awareness of the modes of HIV-1 transmission, and the protection afforded by condom use. Young women are especially susceptible, due to limited capacity to negotiate the circumstances of sexual activity, including the numbers of sexual partners, the types of sexual partners, and whether condoms are used. For example, we have found that HIV-1 infection in young Cambodian female sex workers reaches a prevalence of 26% only 2 to 3 years after sexual debut. Novel concepts for HIV-1 prevention are urgently needed. We propose to evaluate the acceptability and safety of HIV-1 chemoprophylaxis in a double blind phase I/II placebo controlled randomized trial of an antiretroviral drug among HIV-1 uninfected women at risk. Cambodian women who sell beer, or "beer girls," are targeted for this study because they are readily identified in public places, they have stable employment allowing retention in the study, and they are at high risk for HIV-1 infection. Cambodia is ideal for this study at this time because of the recent explosive spread of HIV-1. The selected antiretroviral agent is FDA approved for human use, allows once-a-day dosing, is well tolerated for several years, and is active against most drug resistant HIV-1 strains. The study will also obtain preliminary information regarding HIV-1 incidence and drug efficacy that are required for planning a phase III trial. We estimate that 200 women treated for up to 24 months are sufficient to evaluate safety and acceptability, and may demonstrate efficacy if the prophylactic effect of the drug and the control group HIV-1 incidence prove to be comparable to estimates from non-human primate studies and Cambodian serosurveillance. This staged approach to prevention research is optimized to generate efficacy information in short time frames through use of pilot randomized studies in groups who suffer explosive HIV-1 spread before long term cohorts can be established. Pilot studies that confirm high incidence and acceptable interventions will be expanded into closely monitored efficacy trials. These studies ultimately aim to break the epidemic cycle of HIV-1 by protecting young women, which may also spare their future children and sexual partners.